[Studies on pathophysiology of schizophrenia with a rare variant as a clue]

Schizophrenia is a relatively common and severe mental disorder with complex inheritance patterns; its main manifestations are hallucinations, delusions, and disorganized speech and thinking. The exact etiology of schizophrenia remains unsolved, although pharmacological and biological studies have proposed several hypothetical disease mechanisms and plausible candidate genes for susceptibility. Since the early nineties, extensive genetic studies have been performed on this illness, but there has been no marked progress in the research, and reproducible results have not yet been obtained. Such difficulties in genetic studies of schizophrenia arise from the heterogeneity of this disease. Candidate gene approaches are based on the common disease-common variant hypothesis. However, there is no guarantee that a common variant is shared by patients with heterogeneous pathophysiologies of this disorder. We studied a rare mutation with a major alteration in genetic function based on the common disease-rare variant hypothesis. We detected a novel frameshift mutation of glyoxalase 1 (GLO1) accompanied by a 50% reduction in enzymatic activities in a male schizophrenic patient belonging to a pedigree with multiple affected individuals. GLO1 detoxifies toxic carbonyl compounds that produce advanced glycation end products (AGEs) such as pentosidine by Maillard reaction. AGEs accumulate because of carbonyl stress caused by an increase in reactive carbonyl compounds and their attendant protein modifications. A significant increase in plasma AGEs and a low serum pyridoxal level was seen in our patient. In addition, we found other patients with schizophrenia characterized by the presence of homozygotes of the Ala allele of Glu111Ala in the GLO1 gene and a 16% reduction in the activities that showed high plasma AGEs. As compared to that of the 61 control patients, 45 patients with schizophrenia yielded significantly high levels of AGEs in the plasma and low serum pyridoxal levels. Our findings suggest that GLO1 deficits and carbonyl stress are linked to the development of a certain subtype of schizophrenia. Elevated plasma pentosidine and concomitant low vitamin B₆ levels can be the most cogent and easily measurable biomarkers in schizophrenia and can prove to be helpful for classifying heterogeneous schizophrenia on the basis of biological causes.